E-cigarettes are increasingly used by teenagers, who are particularly vulnerable to the addictive properties of nicotine. With the exclusion of menthol, the use of flavor additives has been banned from traditional cigarettes, while e-cigarettes are marketed in over 7,000 different flavors. Many of those flavors are found in candy and popular soft drinks and, because they are familiar, make e-cigarettes more appealing to adolescents. We hypothesize that flavorants enhance nicotine reward through sensory and/or natural reward mechanisms. As a consequence, flavored e-cigarettes may promote nicotine experimentation, dependence, and eventually, the use of regular cigarettes. Understanding how flavors influence e-cigarette use is important for the implementation of regulatory rules that can reduce potential disease and death deriving from the consumption of this increasingly popular tobacco product. The goal of this application is to compare the rewarding and reinforcing properties of flavored vs. non-flavored e-cigarettes in adolescent mice. Our hypothesis is that flavored e-cigarettes are more rewarding than non-flavored e-cigarettes, and that flavor additives promote and sustain nicotine seeking in adolescents. The first goal is to determine whether sweet flavorants enhance adolescent nicotine reward and promote nicotine self-administration. The second goal is to investigate the possibility that a learned flavor preference, which models exposure to sweetened food and beverages at a young age, will further enhance flavor-induced nicotine reward and self-administration. Finally, we will determine whether exposure to flavored e-cigarettes at young age increases the risk of nicotine abuse in adulthood. These behavioral experiments will be complemented by a series of molecular investigations. First, we will employ in vivo tetrode recording to measure changes in dopamine neuron firing during exposure to flavored and non-flavored e-cig nicotine vapor. Second, we will utilize in vivo voltammetry techniques to quantitatively measure dopamine release in the NAc in response to inhalation of flavored vs.unflavored e-cigarette vapors. Third, we will utilize state-of-the art approaches to determine whether e-cigarette nicotine vapor changes the epigenetic landscape of reward- associated brain areas, and weather fruit flavorants have additive or synergistic effects.